Escherichia coli, and its close relatives, take up two cell wall peptides, L-ala-D-glu-A2pm and L-ala-D-glu-m-A2pm-D-ala, and reuse them, without degradation, for the synthesis of new murein (peptidoglycan). If properly designed, modified cell wall peptides (muropeptides) should also be taken up by these gram-negative bacteria and may function in the same way that B-lactam antibiotics do, by causing the bacteria to form defective murein or by inactivating the enzymes which synthesize the murein. Like B-lactam antibiotics, these peptides should have few side effects on eukaryotes since their action would be directed against murein synthesis and since most of their amino acids and peptide bonds are not found in proteins. The object of this project is to prepare a number of different modified muropeptides and to determine whether they have activity against gram-negative bacteria. The more promising of them would be further characterized as to their mode of action and eventually their usefulness as safe antibacterial agents. There are several functional groups on the muropeptides which could be modified to give them antibacterial activity. For example, the free amino group on the e-x carbon of A2pm is required for linking peptides together in murein and formation of crossbridges between glycan strands. This amino group could easily be removed (by nitrous acid) or chemically altered by a variety of blocking groups and thus reduce crossbridge formation or inactivate the transpeptidases (PBP 1a, 1b, 2 & 3) which form the crossbridges. The 2-carboxyl group on A2pm is required for the addition of the D-ala-D-ala dipeptide to the peptide, and the formation of UDP-MurNAc-1-ala-D-glu-m-A2pm-D-ala-D-ala intermediate. Its modification or substitution by another group could inactivate the ligase which attaches D-ala-D-ala.